Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry.
Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry.
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DOI：
10.1042/bcj20170127
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发表时间：
2017-05-16
期刊：
影响因子：
--
通讯作者：
Williams RL
中科院分区：
文献类型：
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作者：
Masson GR;Maslen SL;Williams RL
直到最近，氢/氘交换质谱（HDX-MS）的主要限制之一是蛋白水解消化提供的肽水平分辨率。这种限制可以通过使用电子转移解离来片段肽，以允许保留氘信号以产生氢/氘交换串联质谱法（HDX-MS/MS）的方式选择性地克服。在这里，我们描述了HDX-MS/MS的应用结构筛选癌基因磷酸肌醇3-激酶催化p110α亚基的抑制剂。HDX-MS/MS分析能够辨别一系列抑制剂共有的保守抑制机制。由于所需的蛋白质量相对较少，因此该技术可用于药物开发以筛选潜在的治疗剂。
Until recently, one of the major limitations of hydrogen/deuterium exchange mass spectrometry (HDX-MS) was the peptide-level resolution afforded by proteolytic digestion. This limitation can be selectively overcome through the use of electron-transfer dissociation to fragment peptides in a manner that allows the retention of the deuterium signal to produce hydrogen/deuterium exchange tandem mass spectrometry (HDX-MS/MS). Here, we describe the application of HDX-MS/MS to structurally screen inhibitors of the oncogene phosphoinositide 3-kinase catalytic p110α subunit. HDX-MS/MS analysis is able to discern a conserved mechanism of inhibition common to a range of inhibitors. Owing to the relatively minor amounts of protein required, this technique may be utilised in pharmaceutical development for screening potential therapeutics.